Controversies and open questions in the definitions and classification of the hypereosinophilic syndromes and eosinophilic leukemias

Eosinophilia is frequently detectable in certain myeloid neoplasms and various reactive conditions, but it may also occur in the absence of an apparent underlying disease, or, rarely, as a paraneoplastic feature with solid tumors. In myeloid neoplasms, eosinophils are considered to belong to the malignant clone in most cases, whereas in all other conditions, eosinophilia is a reactive process triggered by eosinopoietic cytokines. Excessive accumulation of eosinophils, also termed hypereosinophilia (HE), is typically seen in eosinophilic leukemias, but it may also occur in other neoplasms and reactive disorders. HE-related end organ damage may develop in patients with reactive HE but also in those with hematologic malignancies. During the past few years, our knowledge about HE and HE-related organ damage in hematologic and nonhematologic disorders has improved considerably. Moreover, proposals for the definition and classification of eosinophil disorders have been generated by various expert groups and by the World Health Organization (WHO). However, several questions related to eosinophils and HE remain open, and many aspects of the definition and classification of eosinophil disorders and related pathologies remain controversial. In the current article, these open issues are discussed with special reference to the 2008 WHO classification of myeloid neoplasms and other classifications proposed by immunologists and various expert panels, as well as definitions and criteria recently proposed in a multidisciplinary consensus proposal.     

Long‐Term Follow‐Up of CeraOne™ Single‐Implant Restorations: An 18‐Year Follow‐Up Study Based on a Prospective Patient Cohort

Background: Knowledge on long‐term clinical performance of more than 5 years on the single‐implant CeraOne? (Nobel Biocare AB, Gothenburg, Sweden) concept is limited. Purpose: The aim of this study is to report the long‐term clinical performance of the first CeraOne single‐implant restorations, installed 17 to 19 years ago. Materials and Methods: The group comprised 57 patients provided with 65 CeraOne single‐tooth restorations. Sixty‐two all‐ceramic and three metal‐ceramic crowns were cemented between 1989 and 1991. Patients were followed up clinically and with intraoral radiographs at placement, after 1, 5, and between 17 and 19 years after placement. Results: Data were available for altogether 48 patients, followed up on an average time of 18 years. Excluding deceased patients (n = 2) and failed implant patients (n = 2), only five patients were lost to follow‐up (8.8%). Two implants failed, resulting in an 18‐year implant cumulative success rate (CSR) of 96.8%, and altogether eight original single‐crown restorations were replaced (CSR 83.8%). The most common reason for crown replacement was infra‐position of the implant crown (n = 3). Many of the remaining original crowns showed various signs of implant crown infraposition at the termination of the study. In general, the soft tissue at the restorations was assessed to be healthy and comparable with the gingiva at the adjacent natural teeth. Bone levels were on an average stable with only few patients exhibiting bone loss of more than 2 mm during 18 years in function. Conclusion: This long‐term follow‐up study of single‐implant restorations shows encouraging results with few implant failures and minimal bone loss over an 18‐year period. Original single‐crown restorations were replaced more frequently, because of, for example, implant crown infraposition and veneer fractures. The CeraOne concept proved to be a highly predictable and safe prosthodontic treatment.     

Cerebrospinal fluid cathepsin B and S

Cathepsins are increased in the brain of elderly animals. We investigate the presence of cathepsin B and S in human cerebrospinal fluid (CSF) plasma and the associations with cystatin C, age and sex. We measured cathepsin B and S concentrations in CSFs from 118 persons, undergoing elective surgical procedures, with ELISA. Both cathepsin B and cathepsin S were positively correlated with age. No correlation was observed between cathepsin B or S and length, height or body mass index. Both cathepsin B and S were positively correlated to the cystatin C concentration in CSF. Calculated reference intervals were 4,893–17,636 pg/mL for cathepsin B and 2,681–11,459 pg/mL for cathepsin S. Elderly individuals had significantly higher levels of both cathepsin B (r _s = 0.38, p = 0.00002) and cathepsin S (r _s = 0.35, p = 0.0001) in CSF.     

Inverse Association Between Birth Weight,Birth Length and Serum Total Cholesterol in Adulthood

Objectives - To investigate whether impaired fetal growth, measured by low birth weight and short birth length, is linked with raised levels of serum lipids and increased risk and mortality of coronary heart disease. Design - The association between birth length, birth weight, Ponderal Index and total serum cholesterol was examined in 545 Danish men and women aged 31 to 51 years who participated in the Ebeltoft Health Promotion Project in Denmark. Results - No associations were found in women. For men, a negative association was found between birth weight and serum total cholesterol, with a fall in mean serum total cholesterol from 6.03 mmol/l at birth weight below 3300 g to 5.64 mmol/l at birth weight above 4000. A similar association was found between birth length and serum cholesterol, with a mean value of 6.23 mmol/l at birth length below 51 cm and a mean value of 5.56 mmol/l at birth length above 54 cm. No associations were found for Ponderal Index. Between 3% and 8% of the variance in serum total cholesterol could be explained by the statistical models used in this study. Conclusion - Our findings support the hypothesis of a negative association between birth weight, birth length and elevated serum cholesterol in adult life, but only in men.     

In vivo imaging of system xc- as a novel approach to monitor multiple sclerosis

Purpose

Glutamate excitotoxicity contributes to oligodendroglial and axonal damage in multiple sclerosis pathology. Extracellular glutamate concentration in the brain is controlled by cystine/glutamate antiporter (system xc-), a membrane antiporter that imports cystine and releases glutamate. Despite this, the system xc^? activity and its connection to the inflammatory reaction in multiple sclerosis (MS) is largely unknown.

Methods

Longitudinal in vivo magnetic resonance (MRI) and positron emission tomography (PET) imaging studies with 2-[¹⁸F]Fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), [¹¹C]-(R)-(1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide ([¹¹C]PK11195) and (4S)-4-(3-¹⁸F-fluoropropyl)-L-glutamate ([¹⁸F]FSPG) were carried out during the course of experimental autoimmune encephalomyelitis (EAE) induction in rats.

Results

[¹⁸F]FSPG showed a significant increase of system xc^? function in the lumbar section of the spinal cord at 14 days post immunization (dpi) that stands in agreement with the neurological symptoms and ventricle edema formation at this time point. Likewise, [¹⁸F]FDG did not show significant changes in glucose metabolism throughout central nervous system and [¹¹C]PK11195 evidenced a significant increase of microglial/macrophage activation in spinal cord and cerebellum 2 weeks after EAE induction. Therefore, [¹⁸F]FSPG showed a major capacity to discriminate regions of the central nervous system affected by the MS in comparison to [¹⁸F]FDG and [¹¹C]PK11195. Additionally, clodronate-treated rats showed a depletion in microglial population and [¹⁸F]FSPG PET signal in spinal cord confirming a link between neuroinflammatory reaction and cystine/glutamate antiporter activity in EAE rats.

Conclusions

Altogether, these results suggest that in vivo PET imaging of system xc^? could become a valuable tool for the diagnosis and treatment evaluation of MS.

     

Pitch Discrimination in Musicians and Non-Musicians: Effects of Harmonic Resolvability and Processing Effort

Musicians typically show enhanced pitch discrimination abilities compared to non-musicians. The present study investigated this perceptual enhancement behaviorally and objectively for resolved and unresolved complex tones to clarify whether the enhanced performance in musicians can be ascribed to increased peripheral frequency selectivity and/or to a different processing effort in performing the task. In a first experiment, pitch discrimination thresholds were obtained for harmonic complex tones with fundamental frequencies (F0s) between 100 and 500 Hz, filtered in either a low- or a high-frequency region, leading to variations in the resolvability of audible harmonics. The results showed that pitch discrimination performance in musicians was enhanced for resolved and unresolved complexes to a similar extent. Additionally, the harmonics became resolved at a similar F0 in musicians and non-musicians, suggesting similar peripheral frequency selectivity in the two groups of listeners. In a follow-up experiment, listeners’ pupil dilations were measured as an indicator of the required effort in performing the same pitch discrimination task for conditions of varying resolvability and task difficulty. Pupillometry responses indicated a lower processing effort in the musicians versus the non-musicians, although the processing demand imposed by the pitch discrimination task was individually adjusted according to the behavioral thresholds. Overall, these findings indicate that the enhanced pitch discrimination abilities in musicians are unlikely to be related to higher peripheral frequency selectivity and may suggest an enhanced pitch representation at more central stages of the auditory system in musically trained listeners.